A particular focus on the bidirectional interplay between CSCs and the tumor immune microenvironment is focused on, which may provide a conceptual framework for the development of more rational combination strategies, although their clinical benefit remains to be validated.
Abstract
Cancer stem cells (CSCs) represent functionally defined and phenotypically plastic tumor cell populations implicated in therapeutic resistance, relapse, and metastasis. CSC plasticity is regulated through coordinated stemness signaling and epigenetic mechanisms. Canonical stemness-associated pathways, including Wnt, Notch, and Hedgehog, interact with epigenetic programs to maintain dynamic stem-like states and facilitate cellular adaptation to environmental and therapeutic stress. These regulatory networks are also associated with metabolic reprogramming and may support CSC survival under therapeutic and immune pressure. This review summarizes recent advances in our understanding of CSC plasticity, with a particular focus on the bidirectional interplay between CSCs and the tumor immune microenvironment. From a translational perspective, it further summarizes emerging strategies for targeting CSC plasticity in combination with immunotherapy, and discusses the present limitations and challenges of combination strategies. These observations may provide a conceptual framework for the development of more rational combination strategies, although their clinical benefit remains to be validated.
Cancer stem cells (CSCs) are tumor cell subsets with self-renewal, multilineage differentiation, and tumor-initiating capacity that sustain cancer initiation, progression, metastasis, and relapse. Targeting CSCs therefore represents a promising route to improve the durability of cancer treatment. However, translation of this approach into routine care has been slow because of the biological complexity and clinical constraints. This review discusses current concepts of CSC origin and plasticity, the criteria used to define CSCs across different tumor types, and the marker systems as well as high-resolution technologies that are used to track CSC states. Developmental pathways, growth factor and cytokine cascades, as well as microenvironmental and stress responses that control CSC maintenance and therapy resistance are explored with a focus on their tractability as drug targets. We then discuss mechanisms through which CSCs escape chemotherapy, radiotherapy, and targeted agents. We review current efforts to use these pathways in designing small molecules, antibodies, cellular therapies, and vaccines aimed at CSC compartments. Heterogeneity within and between tumors, dynamic interconversion between CSC and non-CSC states, and support from specialized niches are considered as major barriers for clinical trial design, biomarker development, and response assessment. Emerging single-cell, spatial, and lineage tracing approaches, together with organoid and ex vivo platforms, are reviewed as tools that can bridge preclinical models and patient samples and guide the development of CSC-directed combination regimens. The goal is to outline translational principles that can guide future strategies for integrating CSC-focused interventions with established therapies to improve long-term disease control.
Mehreen Ahmed, A. Al-haidari, S. Agarwal et al.· Signal Transduction and Targ...· 0 citations
A comprehensive synthesis of the molecular and microenvironmental mechanisms underlying CSC-driven drug resistance is provided and emerging therapeutic strategies targeting CSC plasticity, niche interactions, metabolic adaptation, and immune evasion are critically discussed.
Hayam Hamdy, Youzhou Li, Chen Li et al.· Molecular Biomedicine· 0 citations
Tumor microenvironment (TME)-induced immunosuppression is a major driver of cancer treatment failure and resistance to immunotherapy. Myeloid-derived suppressor cells (MDSCs) are not only pivotal suppressors of effector immune responses but also central organizers of tumor-supportive metabolic, stromal, and cellular crosstalk. This review systematically summarizes the origin and phenotypic characteristics of MDSCs and the mechanisms governing their recruitment, expansion, and activation within the TME. This review integrates current knowledge of MDSC biology through two complementary frameworks. One framework highlights the bidirectional interactions between MDSCs and immune, tumor, stromal, endothelial, and adipocyte compartments. The other classifies therapeutic approaches according to their mechanisms and translational relevance, including combinations with immunotherapy. We further evaluate clinical translation, including lessons from unsuccessful or inconclusive trials, biomarker gaps, and rational combination strategies. Together, current evidence indicates that MDSCs represent context-dependent therapeutic nodes, while functional reprogramming, spatially resolved profiling, and patient stratification may improve immunotherapy outcomes.
Lisichen Zhu, Hui Liu, Sihan Zhang et al.· Cancer Letters· 0 citations
Current insights into the molecular mechanisms underlying TME remodeling are summarized, including ECM mechanotransduction, hypoxia-driven signaling, hypoxia-driven signaling, epigenetic regulation, metabolic reprogramming, and extracellular vesicle-mediated communication.
Xiaoying Li, Shuang Dai, Dan Cao et al.· Frontiers in Cell and Develo...· 0 citations
Plastic features of BCSCs are summarized, their roles in metastasis and multidrug resistance, microenvironmental regulation and relevant therapeutic targeting strategies are summarized and progress toward subtype-specific combination approaches is indicated.
Mu-Yao Li, Ying Zhou, Xin-Qi Liu et al.· Cancer Advances· 0 citations
Tumor plasticity and microenvironmental heterogeneity are established as an integrated, evolving system that fuels metastasis and limits durable treatment responses.
G. Dagar, M. Dagar, Ashna Gupta et al.· MedComm· 0 citations
